Tobacco use is now recognized as the single most responsible cause of avoidable death worldwide representing approximately 10% of all deaths globally. Directly or indirectly, long term tobacco use has been implicated in complex major health disorders such as cancer, stroke, cardiovascular diseases, and mental disorders. In the USA alone, 30% of all cancer deaths and 87% of all lung cancer deaths are reported to be tobacco-use related. Besides the toll on human health, the estimated annual economic burden of tobacco use had reached over $193 billion both in lost productivity and associated health care costs in the USA. Although significant progress has been made towards the understanding and treatment of nicotine dependence, still approximately 21% of the adult population in the United States continues to smoke, and the increase in disease prevalence and health care expenditure has been positively correlated with smoking. In spite of the sustained national effort that has been undertaken to educate, encourage and help tobacco users to quit and abstain from smoking, only a small percentage of smokers manage to relinquish permanently without an interventional agent. The majority of current therapies for smoking cessation such as nicotine replacement therapy, bupropion and varenicline target the positive reinforcement or the pleasurable effects of nicotine. In contrast, there is currently no therapeutic available for the treatment of nicotine addiction that targets the brain stress systems or the negatively reinforced properties of nicotine addiction. In addition, the efficacy of most of these available therapeutic modalities has not been greatly satisfactory, and is further confounded by serious unwanted side effects such as insomnia, dry mouth, seizure, nausea, headache, psychotropic and gastrointestinal upset. Thus it becomes clear that current smoking cessation therapies are inadequate and that there is a significant need to develop therapeutic agents with new mechanisms of action for more effective treatment of tobacco addiction. An abundance of pharmacological and molecular biology data have implicated the significant roles that Orexin-1 (OX-R1) and Corticotropin-releasing factor receptor-1 (CRF-R1) play in the neurobiology of tobacco addiction and relapse. These data also support the convergent and complementary nature of these receptor signaling pathways. It is then logical to envision a therapeutic approach based on a single agent with a dual CRF-R1 and OX-R1 antagonist profile for nicotine addiction. To date, there is no small molecule with a dual antagonist activity on OX-R1 and CRF-R1. Hence, identifying a drug-like dual OX-R1:CRF-R1 antagonist would have great potential for the treatment of tobacco addiction and would represent a significant advancement in the field. Therefore, the specific aim of this Phase 1 STTR proposal is to identify, characterize, and develop a novel, potent (IC50 <1 uM on both OX- R1:CRF-R1) and selective (>10 x fold over OX-R2 and CRF2) antagonist chemical series, from which we will select a candidate with the best overall biological and physical-chemical properties for a Phase 2 STTR in-vivo study for potential use in the treatment of tobacco addiction and relapse. A successful identification of novel and dual OX-R1:CRF-R1 inhibitors with balanced in-vitro profile in this Phase 1 project would allow us to progress to a final lead optimization campaign focused on identifying pre- clinical leads with well-balanced in vivo pharmacokinetics (PK) parameters for key behavioral as well as pharmacological POC studies in rodent addiction and relapse models during a Phase 2 continuing grant. PUBLIC HEALTH RELEVANCE: Directly or indirectly, long term tobacco use has been implicated in causing complex major health disorders such as cancer, stroke, cardiovascular diseases, and mental disorders that result in otherwise avoidable death worldwide. In the USA alone, 30% of all cancer deaths and 87% of all lung cancer deaths are reported to be related to tobacco use. The economic burden of tobacco use due to associated health-care costs and lost productivity has risen to over $193 billion annually in the US alone. Despite interest in quitting smoking, only a small percentage of smokers manage to relinquish permanently without an interventional agent. Unfortunately, the efficacy of most of the available smoking cessation therapeutic modalities has not been satisfactory, and is further confounded by serious unwanted side effects. It is the aim of this project to discover &develop novel therapeutic agents with unique mechanisms of action for more effective treatment of tobacco addiction and relapse.